Losartan, Suzuki reaction

Alkenylboronic acids and esters are also very useful substrates (Equation 71, Figure 1.38) [405], in particular to access substituted olefins and dienyl moieties commonly encountered in several classes of bioactive natural products [282, 406]. To this end, Kishi and co-workers examined the influence of the base, and developed an optimal variant using thallium hydroxide [281]. Recently, allylic alcohols were found to couple directly with alkyl and alkenyl boronic acids without the aid of a base [407]. In rare cases, the Suzuki reaction has been applied to the use of alkylboronic acids [296, 408], including cyclopropylboronic acids [409]. Hitherto notorious for their tendency to undergo [3-hydride elimination, alkyl bromides are now suitable as electrophiles under carefully optimized conditions that even allow Csp -Csp couplings with alkylboronic acids (Equation 72) [410]. The Suzuki reaction has also been applied very successfully in solid-phase chemistry and combinatorial library synthesis [411]. It has been applied industrially [412], especially in medicinal chemistry, e.g. in the production of the antihypertensive drug losartan [195]. 

FIGURE 9.13. Impurities in the Suzuki cross-coupling reaction to prepare a losartan intermediate... 

The Suzuki cross-coupling reactions have been explored in the synthesis of drugs and related compounds on the laboratory scale but none have been explored on an industrial scale. A few examples given below are AT II antagonist losartan, a COX-2 selective inhibitor, rofecoxib, a highly potent HMG-CoA reductase inhibitor, NK-104, and anticancer agents epothilones A-B. 

The aryltetrazole has hecome a recognizable moiety in new drug candidates as a result of its presence in the commercial antihypertensive drug, Losartan [137]. As in the commercial metric ton synthesis, the preparation of the analog 121 relies on the DoM reaction to give the boronic acid 120 (Scheme 14.26), which, upon the Suzuki-Miyaura cross-coupling with 119, followed by detritylation, affords 121. The ortho-substituted biaryl motif in 121 is also noted in 124, which is obtained by... 

An improved and convergent synthesis of losartan depends upon a Suzuki-coupling reaction. 

The Suzuki coupling can be applied on simple and more complex substrates. Industrial applications can be found in the synthesis of the drug losartan or the fungizide boscalid. " Gaukroger et al. synthesized both Z and E isomers of anticancer drug (Z)-combretastatin A-4 via a Suzuki cross-coupling reaction of an arylboronic acid and either (Z)- or ( )-vinyl bromide (Scheme 5-59). ... 

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